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KDR AND REVERSES HINDLIMB ISCHEMIA
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Publication Only ACTIVATION OF FRACTALKINE/CX3CR1 BY VASCULAR ENDOTHELIAL CELLS INDUCES ANGIOGENESIS THROUGH VEGF-A/KDR AND REVERSES HINDLIMB ISCHEMIA
K. Han, J. Ryu, S. Lim. ASAN Institutue for Life Science/ASAN Medical Center, Seoul, Sonpa-gu, Korea Objective: Fractalkine (Fkn) induces angiogenesis. Results: Fkn induced new vessel formation on CAM assay through CX3CR1 activation. Immunoblotting and EMSA showed that Fnk up regulated HIF-1α) by cultured human aortic endothelial cells, which in turn induced expression of VEGF-A, through p42/44 MAPK pathway. In vivo Fkn-induced angiogenesis on CAM was completely abrogated by functional inhibition of KDR and Rho GTPase. Overt angiogenesis was developed in the Fkn-mixed Matrigel plug implanted to C57/BL6 mice with CX3CR1(-/-) bone marrow-derived cells, suggesting CX3CR1 activation in ECs is sufficient for Fnk-induced angiogenesis in vivo. The model of rat hindlimb ischemia was significantly improved by injection of whole-length Fkn protein. Conclusions: Fkn-induced activation of CX3CR1 by ECs induces in vivo angiogenesis, first, the induction of HIF-1α and VEGF-A gene expression after CX3CR1 activation, and second, VEGF-A/KDR-induced angiogenesis. The potent induction of angiogenesis by Fkn can be used as a therapeutic strategy for alleviating peripheral ischemia. 113
THE BEST ANTHROPOMETRIC INDEX FOR PREDIC OF HYPERTENSION, DIABETES AND METABOLIC SYNDROME IN IRANIAN ADULT POPULATION
M. Safarian 1 , M. Azimi-Nezhad 2 , M. Ghayour-Mobarhan 1,2 , M. Rajabi-Moghaddam 2 , A. Gholami 2 , H. Esmailli 3 . 1 Biochemistry and Nutrition Department,Mashhad University of Medical Sciences, Mashhad, Iran; 2 Avicenna Research Institute,Mashhad University of Medical Sciences, Mashhad, Iran; 3 Community Health and Biostatistic Department,Mashhad University of Medical Sciences, Mashhad, Iran Background: The aim of the present study was to define optimal anthropometric measures and their cutoff values in association with diabetes mellitus, hypertension and metabolic syndrome. Materials and Methods: A total of 4990 persons (2487 men and 2503 women) aged 15-65 years from rural and urban area of Khorasan province were recruited using a cluster-stratified sampling. Using standard methods anthropometric measures including weight, height and waist and fasting serum sample were collected and detailed demographic questionnaire were filed. The method of Receiver operating characteristics (ROC) analysis was use to define optimal anthropometric cut-off values. Results: The cut-off values of waist circumference to predict hypertension, diabetes and metabolic syndrome among men were 85.1cm (sensitivity = 64.2% & specificity = 61.8%), 91.1cm (sensitivity = 68.1% & specificity = 64.5%) and 94.1 (sensitivity = 95.4% & specificity = 93.3%) and for women were 89.1cm (sensitivity = 68.4% & specificity = 61.5%), 94.8cm (sensitivity = 67.9% & specificity = 61.3%)and 89.25 (sensitivity = 78% & specificity = 73.2%) respectively (p< 0.05). Conclusions: There was a significant correlation between hypertension, Diabetes and metabolic syndrome with waist circumference, particularly in women, and with waist height ratio in both genders. Also the waist circumference cutoffs were higher for women than men for all these three disorders except for that of metabolic syndrome. 114
ABDOMINAL ADIPOSITY ACCOUNTS FOR THE ASSOCIATION OF ANDROGEN DEFICIENCY WITH METABOLIC SYNDROME IN MIDDLE-AGED JAPANESE MEN
M. Akishita, S. Mochizuki, Y. Yamada, K. Iijima, M. Eto, Y. Ouchi. Department of Geriatric Medicine, University of Tokyo, Tokyo, Japan Background: Epidemiological studies have shown that androgen deficiency is associated with metabolic syndrome (MS) in men, but the underlying mechanism remains unknown. We investigated whether testosterone level is independently related to the factors of MS in middle-aged Japanese men. Methods: A cross-sectional survey was conducted in 118 men (mean age ± SD = 47±11 years, 30-69 years). Evaluation of MS and blood sampling were performed after 12-hour fast in the morning, and the
relationship between plasma hormone levels and MS was analyzed. MS was defined using the International Diabetes Federation criteria. Results: Low total testosterone was associated with MS (odds ratio of 1.61 by quartile of testosterone, p<0.01), while dehydroepiandrosteronesulfate, estradiol and cortisol were not. Age-adjusted regression analysis revealed that total testosterone was significantly related to the parameters of obesity (ß=-0.378, –0.366 and –0.334 for waist circumference, body mass index and visceral fat area measured using CT), hypertension (ß=-0.315 and –0.226 for systolic and diastolic blood pressure), dyslipidemia (ß=-0.207 and –0.237 for triglycerides and free fatty acids) and insulin resistance (ß=-0.231 and –0.305 for fasting plasma glucose and HOMA-IR), and to adiponectin (ß=0.265). Interestingly, testosterone was not related to the parameters of MS after either of the parameters of obesity was added to the models, whereas testosterone was still significantly related to the parameters of obesity. Conclusions: These results confirmed that low testosterone level was associated with MS in middle-aged Japanese men, and suggest that abdominal adiposity accounts for the association of androgen deficiency with the factors of MS. 115
CORONARY FLOW RESERVE DECREASES DURING MENOPAUSE
S. Eroglu, E. Sade, S. Ozbicer, O. Demir, H. Bozbas, H. Muderrisoglu. Department of Cardiology, University of Baskent, Faculty of Medicine, Ankara, Turkey Background and aim: Menopause is a related to the development of coronary artery disease in women. In this study we aimed to investigate whether menopause impairs coronary flow reserve (CFR). Method: In all 60 women (42 postmenopausal, 26 non-menopausal; mean age 54.1±9.1 years) with normal coronary angiography findings were consecutively studied. All subjects underwent transthoracic echocardiography the day after the coronary angiography. We measured coronary diastolic peak flow velocities at baseline and after dipyridamole infusion (0.56 mg/kg over 4 minute). CFR was calculated as the ratio of hyperemic to baseline diastolic peak velocities. Results: Postmenopausal women were older than non-menopausal women (58.6±6.5 vs 43.5±4.4 years p<0.001). CFR was significantly reduced in postmenopausal women as compared with non-menopausal women (2.0±0.5 vs 2.7±0.6 p<0.001). In stepwise regression analysis including risk factors that are known to be associated with atherosclerosis (age, smoking, blood pressure, glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride and CRP) menopause (P<0.001, [95%CI, 2.7-6.7]) and age were the only independent factors related to CFR Conclusion: Menopause is an independent risk factor that impairs CFR in women with normal epicardial coronary arteries. 116
SIGNIFICANCE OF SMALL DENSE LOW-DENSITY LIPOPROTEINS IN CORONARY HEART DISEASE
Y. Ito 1 , S. Koba 2 , T. Hirano 3 , Y. Yokota 2 , F. Tsunoda 2 , Y. Ban 2 , T. Sato 2 , M. Shoji 2 , H. Suzuki 2 , E. Geshi 2 , T. Katagiri 2 . 1 Reseacrh and Development Department, Denka Seiken Co., Ltd., Tokyo, Japan; 2 The Third Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan; 3 The First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan Low-density lipoprotein (LDL) particles are heterogeneous with respect to their size, density, and lipid composition, and the size of LDL particles is chiefly determined by their lipid contents. Small dense LDL particles have been suggested to be highly atherogenic compared to large buoyant LDL. Our case-control studies have shown that the LDL particle size determined by gradient gel electrophoresis was remarkably smaller in patients with coronary heart disease (CHD), irrespective of the presence of diabetes and the differences in clinical situation and severity of CHD. In addition, small dense LDL-cholesterol concentration evaluated by heparin magnesium precipitation was significantly higher in severe stable CHD and acute coronary syndrome compared with non-CHD subjects and patients with mild CHD, while large LDL-cholesterol estimated by subtracting the small dense LDL-cholesterol concentration from the LDL-cholesterol concentration, were somewhat lower in stable CHD compared with healthy subjects. Furthermore, reduced LDL particle size and elevated small dense LDL-cholesterol levels were significantly associated with metabolic dyslipidemia in Metabolic syndrome. These suggest that the predominance of
77th Congress of the European Atherosclerosis Society, April 26–29, 2008, Istanbul, Turkey
Publication Only ACTIVATION OF FRACTALKINE/CX3CR1 BY VASCULAR ENDOTHELIAL CELLS INDUCES ANGIOGENESIS THROUGH VEGF-A/KDR AND REVERSES HINDLIMB ISCHEMIA
K. Han, J. Ryu, S. Lim. ASAN Institutue for Life Science/ASAN Medical Center, Seoul, Sonpa-gu, Korea Objective: Fractalkine (Fkn) induces angiogenesis. Results: Fkn induced new vessel formation on CAM assay through CX3CR1 activation. Immunoblotting and EMSA showed that Fnk up regulated HIF-1α) by cultured human aortic endothelial cells, which in turn induced expression of VEGF-A, through p42/44 MAPK pathway. In vivo Fkn-induced angiogenesis on CAM was completely abrogated by functional inhibition of KDR and Rho GTPase. Overt angiogenesis was developed in the Fkn-mixed Matrigel plug implanted to C57/BL6 mice with CX3CR1(-/-) bone marrow-derived cells, suggesting CX3CR1 activation in ECs is sufficient for Fnk-induced angiogenesis in vivo. The model of rat hindlimb ischemia was significantly improved by injection of whole-length Fkn protein. Conclusions: Fkn-induced activation of CX3CR1 by ECs induces in vivo angiogenesis, first, the induction of HIF-1α and VEGF-A gene expression after CX3CR1 activation, and second, VEGF-A/KDR-induced angiogenesis. The potent induction of angiogenesis by Fkn can be used as a therapeutic strategy for alleviating peripheral ischemia. 113
THE BEST ANTHROPOMETRIC INDEX FOR PREDIC OF HYPERTENSION, DIABETES AND METABOLIC SYNDROME IN IRANIAN ADULT POPULATION
M. Safarian 1 , M. Azimi-Nezhad 2 , M. Ghayour-Mobarhan 1,2 , M. Rajabi-Moghaddam 2 , A. Gholami 2 , H. Esmailli 3 . 1 Biochemistry and Nutrition Department,Mashhad University of Medical Sciences, Mashhad, Iran; 2 Avicenna Research Institute,Mashhad University of Medical Sciences, Mashhad, Iran; 3 Community Health and Biostatistic Department,Mashhad University of Medical Sciences, Mashhad, Iran Background: The aim of the present study was to define optimal anthropometric measures and their cutoff values in association with diabetes mellitus, hypertension and metabolic syndrome. Materials and Methods: A total of 4990 persons (2487 men and 2503 women) aged 15-65 years from rural and urban area of Khorasan province were recruited using a cluster-stratified sampling. Using standard methods anthropometric measures including weight, height and waist and fasting serum sample were collected and detailed demographic questionnaire were filed. The method of Receiver operating characteristics (ROC) analysis was use to define optimal anthropometric cut-off values. Results: The cut-off values of waist circumference to predict hypertension, diabetes and metabolic syndrome among men were 85.1cm (sensitivity = 64.2% & specificity = 61.8%), 91.1cm (sensitivity = 68.1% & specificity = 64.5%) and 94.1 (sensitivity = 95.4% & specificity = 93.3%) and for women were 89.1cm (sensitivity = 68.4% & specificity = 61.5%), 94.8cm (sensitivity = 67.9% & specificity = 61.3%)and 89.25 (sensitivity = 78% & specificity = 73.2%) respectively (p< 0.05). Conclusions: There was a significant correlation between hypertension, Diabetes and metabolic syndrome with waist circumference, particularly in women, and with waist height ratio in both genders. Also the waist circumference cutoffs were higher for women than men for all these three disorders except for that of metabolic syndrome. 114
ABDOMINAL ADIPOSITY ACCOUNTS FOR THE ASSOCIATION OF ANDROGEN DEFICIENCY WITH METABOLIC SYNDROME IN MIDDLE-AGED JAPANESE MEN
M. Akishita, S. Mochizuki, Y. Yamada, K. Iijima, M. Eto, Y. Ouchi. Department of Geriatric Medicine, University of Tokyo, Tokyo, Japan Background: Epidemiological studies have shown that androgen deficiency is associated with metabolic syndrome (MS) in men, but the underlying mechanism remains unknown. We investigated whether testosterone level is independently related to the factors of MS in middle-aged Japanese men. Methods: A cross-sectional survey was conducted in 118 men (mean age ± SD = 47±11 years, 30-69 years). Evaluation of MS and blood sampling were performed after 12-hour fast in the morning, and the
relationship between plasma hormone levels and MS was analyzed. MS was defined using the International Diabetes Federation criteria. Results: Low total testosterone was associated with MS (odds ratio of 1.61 by quartile of testosterone, p<0.01), while dehydroepiandrosteronesulfate, estradiol and cortisol were not. Age-adjusted regression analysis revealed that total testosterone was significantly related to the parameters of obesity (ß=-0.378, –0.366 and –0.334 for waist circumference, body mass index and visceral fat area measured using CT), hypertension (ß=-0.315 and –0.226 for systolic and diastolic blood pressure), dyslipidemia (ß=-0.207 and –0.237 for triglycerides and free fatty acids) and insulin resistance (ß=-0.231 and –0.305 for fasting plasma glucose and HOMA-IR), and to adiponectin (ß=0.265). Interestingly, testosterone was not related to the parameters of MS after either of the parameters of obesity was added to the models, whereas testosterone was still significantly related to the parameters of obesity. Conclusions: These results confirmed that low testosterone level was associated with MS in middle-aged Japanese men, and suggest that abdominal adiposity accounts for the association of androgen deficiency with the factors of MS. 115
CORONARY FLOW RESERVE DECREASES DURING MENOPAUSE
S. Eroglu, E. Sade, S. Ozbicer, O. Demir, H. Bozbas, H. Muderrisoglu. Department of Cardiology, University of Baskent, Faculty of Medicine, Ankara, Turkey Background and aim: Menopause is a related to the development of coronary artery disease in women. In this study we aimed to investigate whether menopause impairs coronary flow reserve (CFR). Method: In all 60 women (42 postmenopausal, 26 non-menopausal; mean age 54.1±9.1 years) with normal coronary angiography findings were consecutively studied. All subjects underwent transthoracic echocardiography the day after the coronary angiography. We measured coronary diastolic peak flow velocities at baseline and after dipyridamole infusion (0.56 mg/kg over 4 minute). CFR was calculated as the ratio of hyperemic to baseline diastolic peak velocities. Results: Postmenopausal women were older than non-menopausal women (58.6±6.5 vs 43.5±4.4 years p<0.001). CFR was significantly reduced in postmenopausal women as compared with non-menopausal women (2.0±0.5 vs 2.7±0.6 p<0.001). In stepwise regression analysis including risk factors that are known to be associated with atherosclerosis (age, smoking, blood pressure, glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride and CRP) menopause (P<0.001, [95%CI, 2.7-6.7]) and age were the only independent factors related to CFR Conclusion: Menopause is an independent risk factor that impairs CFR in women with normal epicardial coronary arteries. 116
SIGNIFICANCE OF SMALL DENSE LOW-DENSITY LIPOPROTEINS IN CORONARY HEART DISEASE
Y. Ito 1 , S. Koba 2 , T. Hirano 3 , Y. Yokota 2 , F. Tsunoda 2 , Y. Ban 2 , T. Sato 2 , M. Shoji 2 , H. Suzuki 2 , E. Geshi 2 , T. Katagiri 2 . 1 Reseacrh and Development Department, Denka Seiken Co., Ltd., Tokyo, Japan; 2 The Third Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan; 3 The First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan Low-density lipoprotein (LDL) particles are heterogeneous with respect to their size, density, and lipid composition, and the size of LDL particles is chiefly determined by their lipid contents. Small dense LDL particles have been suggested to be highly atherogenic compared to large buoyant LDL. Our case-control studies have shown that the LDL particle size determined by gradient gel electrophoresis was remarkably smaller in patients with coronary heart disease (CHD), irrespective of the presence of diabetes and the differences in clinical situation and severity of CHD. In addition, small dense LDL-cholesterol concentration evaluated by heparin magnesium precipitation was significantly higher in severe stable CHD and acute coronary syndrome compared with non-CHD subjects and patients with mild CHD, while large LDL-cholesterol estimated by subtracting the small dense LDL-cholesterol concentration from the LDL-cholesterol concentration, were somewhat lower in stable CHD compared with healthy subjects. Furthermore, reduced LDL particle size and elevated small dense LDL-cholesterol levels were significantly associated with metabolic dyslipidemia in Metabolic syndrome. These suggest that the predominance of
77th Congress of the European Atherosclerosis Society, April 26–29, 2008, Istanbul, Turkey